Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign ...(self‐limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later‐onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.
This randomized trial showed that two different doses of oral cannabidiol resulted in greater reductions in drop-seizure and total-seizure frequencies than placebo among patients with the ...Lennox–Gastaut syndrome, a severe developmental epileptic encephalopathy.
Summary
The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms ...following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self‐limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
Summary
Objective
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to ...drug‐resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non‐SCN1A genes in DS, and what is known about phenotypic similarities and differences. We discuss whether these are best thought of as minority causes of DS, or as similar but distinct conditions.
Methods
Based on a review of literature, a list of genes linked to DS was compiled and PubMed was searched for reports of DS‐like phenotypes arising from variants in each. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene.
Results
Genes that have been reported to cause DS‐like phenotypes include SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2. Many of these genes, however, appear to be associated with their own, different, clinical picture. Other candidate genes for DS have been reported, but there is currently an insufficient body of literature to support their causative role.
Significance
Although most cases of DS arise from SCN1A variants, numerous other genes cause encephalopathies that are clinically similar. Increasingly, a tendency is noted to define newly described epileptic disorders primarily in genetic terms, with clinical features being linked to genotypes. As genetic diagnosis becomes more readily available, its potential to guide pathophysiologic understanding and therapeutic strategy cannot be ignored. Clinical assessment remains essential; the challenge now is to develop a gene‐based taxonomy that complements traditional syndromic classifications, allowing elements of both to inform new approaches to treatment.
Summary
Mutations in the gene encoding the α1 subunit of the voltage gated sodium channel (SCN1A) are associated with several epilepsy syndromes, ranging from relatively mild phenotypes found in ...families with genetic epilepsy with febrile seizures plus (GEFS+) to the severe infant‐onset epilepsy Dravet syndrome. Evidence has emerged of the consequences of SCN1α dysfunction in different neuronal networks across the brain pointing toward a channelopathy model causing the neurologic features of Dravet syndrome that is beyond purely seizure related damage. A genetic change will present according to its severity, the genetic background of the individual, and environmental factors, and will affect a variety of neuronal networks according to channel distribution. This already‐vulnerable system may be susceptible to secondary aggravating events such as status epilepticus. The channelopathy model implies that pharmacologic treatment and the restoration of impaired γ‐aminobutyric acid (GABA)ergic neurotransmission might not only help prevent seizures but might affect the comorbidities of the syndrome. This critical review explores recent evidence relating to the pathogenicity of SCN1A mutations in Dravet syndrome and the effect these have on the wider disease phenotype and discusses whether knowledge of specific genotypes can influence clinical practice. Genetic technology is currently advancing at unprecedented speed and will increase our knowledge of new genes and interacting genetic networks. Clinicians and geneticists will have to work in close collaboration to guarantee good delivery and counseling of genetic testing results.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section here
Summary
The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can ...have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) “partial” becomes “focal”; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic–clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic–atonic, myoclonic–tonic–clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.
Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be ...electrographic‐only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults. A Neonatal Seizures Task Force was established by the International League Against Epilepsy (ILAE) to develop a modification of the 2017 ILAE Classification of Seizures and Epilepsies, relevant to neonates. The neonatal classification framework emphasizes the role of electroencephalography (EEG) in the diagnosis of seizures in the neonate and includes a classification of seizure types relevant to this age group. The seizure type is determined by the predominant clinical feature. Many neonatal seizures are electrographic‐only with no evident clinical features; therefore, these are included in the proposed classification. Clinical events without an EEG correlate are not included. Because seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized is unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), non‐motor (autonomic, behavior arrest), or sequential presentation. The classification allows the user to choose the level of detail when classifying seizures in this age group.
Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with multiple seizure types starting in childhood, a typical slow ...spike-wave pattern on electroencephalogram, and cognitive dysfunction.
We performed a systematic literature review according to the PRISMA guidelines to identify, synthesize and appraise the burden of illness in LGS (including "probable" LGS). Studies were identified by searching MEDLINE, Embase and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos. The outcomes were epidemiology (incidence, prevalence or mortality), direct and indirect costs, healthcare resource utilization, and patient and caregiver health-related quality of life (HRQoL).
The search identified 22 publications evaluating the epidemiology (n = 10), direct costs and resource (n = 10) and/or HRQoL (n = 5). No studies reporting on indirect costs were identified. With no specific ICD code for LGS in many regions, several studies had to rely upon indirect methods to identify their patient populations (e.g., algorithms to search insurance claims databases to identify "probable" LGS). There was heterogeneity between studies in how LGS was defined, the size of the populations, ages of the patients and length of the follow-up period. The prevalence varied from 4.2 to 60.8 per 100,000 people across studies for probable LGS and 2.9-28 per 100,000 for a confirmed/narrow definition of LGS. LGS was associated with high mortality rates compared to the general population and epilepsy population. Healthcare resource utilization and direct costs were substantial across all studies. Mean annual direct costs per person varied from $24,048 to $80,545 across studies, and home-based care and inpatient care were significant cost drivers. Studies showed that the HRQoL of patients and caregivers was adversely affected, although only a few studies were identified. In addition, studies suggested that seizure events were associated with higher costs and worse HRQoL. The risk of bias was low or moderate in most studies.
LGS is associated with a significant burden of illness featuring resistant seizures associated with higher costs and worse HRQoL. More research is needed, especially in evaluating indirect costs and caregiver burden, where there is a notable lack of studies.
In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the “genetic generalized epilepsies” (GGEs), which contained the “idiopathic generalized epilepsies” ...(IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic–clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE’s Task Force on Nosology and Definitions (2017–2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic‐clonic and myoclonic‐tonic‐clonic seizures, with 2.5–5.5 Hz generalized spike‐wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.
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